PT  - JOURNAL ARTICLE
AU  - Hongyu Zhang
AU  - Chunlei Zhang
AU  - Jean Vincent
AU  - Diana Zala
AU  - Caroline Benstaali
AU  - Matthieu Sainlos
AU  - Dolors Grillo-Bosch
AU  - Yoon Cho
AU  - Denis J. David
AU  - Frederic Saudou
AU  - Yann Humeau
AU  - Daniel Choquet
TI  - Pharmacological modulation of AMPA receptor surface diffusion restores hippocampal synaptic plasticity and memory in Huntington’s disease
AID  - 10.1101/297069
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 297069
4099  - http://biorxiv.org/content/early/2018/04/07/297069.short
4100  - http://biorxiv.org/content/early/2018/04/07/297069.full
AB  - Impaired hippocampal synaptic plasticity is increasingly considered to play an important role in cognitive impairment in Huntington’s disease (HD). However, the molecular basis of synaptic plasticity defects is not fully understood. Combining live-cell nanoparticle tracking and super-resolution imaging, we show that dysregulation of AMPA receptors (AMPARs) surface diffusion represents a molecular basis underlying the aberrant hippocampal synaptic plasticity during HD. AMPARs surface diffusion is increased in various HD neuronal models, which results in the failure of AMPARs surface stabilization after long-term potentiation (LTP) stimuli. This appears to result from a defective brain-derived neurotrophic factor (BDNF) - tyrosine receptor kinase B (TrkB) - Ca2+/calmodulin-dependent protein kinase II (CaMKII) signaling pathway that impacts the interaction between the AMPAR auxiliary subunit stargazin and postsynaptic density protein 95 (PSD-95). Notably, the disturbed AMPAR surface diffusion is rescued, via BDNF signaling pathway and by the antidepressant tianeptine. Tianeptine also restores the impaired LTP and hippocampus-dependent memory as well as anxiety/depression-like behavior in different HD mouse models. We thus unveil a mechanistic framework underlying hippocampal synaptic and memory dysfunction and propose a new perspective in HD treatment by targeting AMPAR surface diffusion.